Various complexes of monodentate and bidentate ligands with technetium have been made and studied. These complexes generally were made for use in studies to determine the various oxidation states of technetium and for other research regarding the structure of such complexes and metal-coordination chemistry. Such studies have been reported in, for instance, Chemistry and Industry, pp. 347-8 (Mar. 26, 1960); J. Inorg. Nucl. Chem., Vol. 28, pp. 2293-96 (1966); Aust. J. Chem., 23 pp. 453-61 (1970); Inorganic Chem., Vol. 16, No. 5, pp. 1041-48 (1977); J. Inorg. Nucl. Chem., Vol. 39, pp. 1090-92 (1977); and J.C.S. Dalton, pp. 125-30 (1976).
Recently, in a presentation to the American Pharmaceutical Association, E. A. Deutsch disclosed that certain complexes of DIARS, i.e. ##STR1## and Tc-99m, and certain complexes of DMPE, i.e. (CH.sub.3).sub.2 PCH.sub.2 CH.sub.2 P(CH.sub.3).sub.2 and Tc-99m, may be useful as radiodiagnostic agents for myocardial or hepatobiliary imaging. [.sup.99m Tc-(DMPE).sub.2 Cl.sub.2 ]+ and [.sup.99m Tc-(DIARS).sub.2 ]+ were prepared by Deutsch by heating in an open flask a reaction mixture containing the appropriate hydrogen halide in aqueous alcohol solution, .sup.99m Tc-sodium pertechnetate, and ortho-phenylenebis(dimethylarsine), i.e. DIARS, or bis-(1,2-dimethylphosphino)ethane, i.e. DMPE. The reaction was reported to take about 30 minutes. The labelled complex was then purified by chromatographic methods involving ion exchange columns.
The labelled complex produced according to the procedure of Deutsch has several practical disadvantages. The procedure requires handling several ingredients including an organic solvent to make the reaction mixture and then purifying the resulting radiolabelled complex by chromatography. Each of these handling steps can contaminate the system and final product. The purification step further requires additional time for preparation of the final product. These steps require a skilled technician and are performed at the site of use, just prior to use. Thus, a complex, time consuming chemical preparation is required during which sterility of ingredients and containers is difficult to maintain. Thus, to assure freedom from contamination, a final sterilization step is required, which further adds to preparation time. Because Tc-99m has a short half-life, lengthy preparation methods are undesirable. Thus, the complexity of the preparation, both with regard to maintaining sterile conditions and to purification of the .sup.99m Tc-labelled complex make the Deutsch procedure undesirable.
It would be highly desirable to have a sterilized kit with all the necessary materials prepared by the manufacturer, to which only the Tc-99m need be added at the site of use to produce the desired labelled complex directly in high enough yield to obviate the need for purification. It would also be desirable for the kit materials to be in a closed container or vial, pre-sterilized, so that the only step to be performed at the site of use would be the addition of the radionuclide. To increase stability and shelf-life of the kit, it would be highly desirable that the materials be readily lyophilized, preferably from an aqueous solution.
By achieving the desirable features outlined above, a convenient-to-use heart imaging radiopharmaceutical agent would be provided that is capable of concentrating in healthy heart tissue to provide a negative image of an infarct, damaged or ischemic tissue.
A copending application, Ser. No. 311,770, filed Oct. 15, 1981 in the name of Vinayakam Subramanyam, which is hereby incorporated by reference, describes an acid salt of a mono or polydentate ligand that is water soluble, stable in a lyophilized state, and is capable of binding with Tc-99m to form a cationic complex. The acid salt may be generally represented by the formula: ##STR2## wherein:
i is an integer from 1 to 6;
R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups, and R plus R.sup.i may be taken together to form a cyclic compound or separately to form a linear compound;
Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.5 and Y.sup.6 are independently selected from substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups;
A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5 and A.sup.6 are the same or different neutral donor atoms, each having a free electron pair available for accepting a proton to provide a charged ligand or for complexing with Tc-99m or Tc-99 to form a cationic complex;
Z is preferably a parenterally acceptable anion;
k.sub.1, k.sub.2, k.sub.3, k.sub.4, k.sub.5 and k.sub.6 are each independently zero or one; PA1 n.sub.9 and n.sub.10 are integers selected from 1 to about 3, where n.sub.9 =j+j'+j" and the charge represented by n.sub.10 Z is equal in magnitude and opposite in sign to +n.sub.9.
n.sub.1, n.sub.2, n.sub.3, n.sub.4, n.sub.5 and n.sub.6 are independently 0 or 1; and
n.sub.7 and n.sub.8 are integers from 1 to 6 where ##EQU1## and the charge represented by n.sub.8 Z is equal in magnitude and opposite in sign to +n.sub.7 ; or ##STR3## wherein:
R, R' and R" are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocylcloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups;
A, A' and A" are independently selected from the group of neutral donor atoms having a pair of electrons available for accepting a proton to provide a charged ligand or for complexing with Tc-99m or Tc-99 to form a cationic complex;
j, j' and j" are independently 0 or 1;
n, n' and n" are independently the integer 1 or 2;
Z is the same as defined above;
These acid salts are normally solid compounds, water-soluble, readily lyophilized, and capable of reducing pertechnetate and binding with technetium to form stable cationic complexes.